This invention relates to vitamin D derivatives with substituents at C-25 of general formula I 
in which
Y1 means a hydrogen atom, a hydroxyl group, an alkanoyloxy group with 1 to 12 C atoms or an aroyloxy group,
Y2 means a hydrogen atom or an alkanoyl group with 1 to 12 C atoms or an aroyl group,
R1 and R2 each mean a hydrogen atom or together an exocyclic methylene group,
R3 and R4, independently of one another, mean a hydrogen atom, a chlorine or fluorine atom, an alkyl group with 1 to 4 carbon atoms, together a methylene group or together with quaternary carbon atom 20 a 3- to 7-membered, saturated or unsaturated carbocyclic ring,
A and B together mean a keto group or A means a group ORxe2x80x2 and B means a hydrogen atom or B means a group ORxe2x80x2 and A means a hydrogen atom, whereby Rxe2x80x2 is a hydrogen atom or a straight-chain or branched-chain, saturated alkanoyl group with up to 9 carbon atoms or an aroyl group,
R5 and R6 at the same time each mean a hydrogen atom, a chlorine or fluorine atom, a trifluoromethyl group, a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 4 carbon atoms or R5 and R6 together with carbon atom 25 mean a 3- to 7-membered, saturated or unsaturated carbocyclic ring and
Z means a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 12 carbon atoms, which can also have a carbocyclic or heterocyclic partial structure and at any positions can exhibit keto groups, hydroxy groups (in xcex1- or xcex2-position) that in turn can be etherified or esterified, amino groups, halogen atoms or carboxylic acid ester or amide units and is linked by a carbonyl group, a hydroxymethylene group or an ethenediyl unit Cxe2x80x94CHxe2x95x90CHxe2x80x94, E- or Z-geometry) with carbon atom 25,
and processes for their production, intermediate products for these processes, pharmaceutical preparations that contain these compounds as well as their use for the production of pharmaceutical agents.
The alkanoyl or alkanoyloxy groups with 1 to 12 C atoms that are possible for radicals Y1 and Y2 are derived especially from saturated carboxylic acids. These radicals can be cyclic, acyclic, carbocyclic or heterocyclic. The preferred radicals are derived from C1 to C9, especially C2 to C5 alkanecarboxylic acids, such as, for example, acetyl(oxy), propionyl(oxy), butyryl(oxy).
As aroyl(oxy) groups, the benzoyl(oxy) groups and substituted benzoyl(oxy) groups are preferred.
For R3 and R4, the following preferred combinations apply: R3=H, R4=methyl or R3=methyl, R4=H; R3=F, R4=methyl or R3=methyl, R4=F; R3, R4=methyl; R3 and R4 together form a methylene group or together with tertiary carbon atom 20 form a cyclopropyl ring.
For A and B, the following preferred combinations apply:
A=OH, B=H or A=H, B=OH and A and B form a carbonyl group.
For R5 and R6, the following preferred combinations apply:
R5, R6=methyl or ethyl; R5 and R6 together with carbon atom 25 form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
Especially preferred are the cases R5, R6=methyl, and R5 and R6 together with carbon atom 25 form a cyclopropyl ring.
For Z, the following preferences apply:
Z=xe2x80x94C(O)xe2x80x94R9 or Z=xe2x80x94CH(OH)xe2x80x94R9 (xcex1- or xcex2-hydroxy), whereby R9 is a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 12 carbon atoms or else R9 can be carbocyclic or heterocyclic or can exhibit such partial structures and can also be perfluorinated.
For R9, the following special preferences apply:
R9=methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, i-propyl, i-butyl, t-butyl, 1-butenyl, 1-pentenyl, 1-butinyl, 1-pentinyl, phenyl, furanyl, pyridinyl, trifluoromethyl, perfluoroethyl, perfluoropropyl, perfluorobutyl, perfluoropentyl or perfluorohexyl.
Also, for Z, the following preference applies: 
with R12=C1-C10 alkyl or alkoxy (straight-chain, branched, saturated, unsaturated, cyclic) or 
with R13=C1-C10 alkyl (straight-chain, branched, saturated, unsaturated, cyclic), whereby R13 can also have substituents (keto groups, hydroxy groups, carboxylic acid esters, carboxylic acid amides, halogens).
Especially preferred according to this invention are the following compounds:
(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-benzoyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-benzoyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(2-furanylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(2-furanylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(2,2-dimethyl-1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(2,2-dimethyl-1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(2-pyridinylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(2-pyridinylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-oxo-2-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-oxo-2-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxo-2-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxo-2-hexinyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(cyclopropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(cyclopropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-ethoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-ethoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-propoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-propoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-butoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-butoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-[1S,3R,24S,25(S)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-[1S,3R,24S,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-[1S,3R,24R,25(S)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-[1S,3R,24R,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-[1S,3R,24S,25(S)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-[1S,3R,24S,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-[1S,3R,24R,25(S)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-[1S,3R,24R,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(trifluoroacetyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(trifluoroacetyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(perfluoroethylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(perfluoroethylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(perfluoropropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(perfluoropropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(perfluorobutylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(perfluorobutylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(perfluoropentylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(perfluoropentylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-(perfluorohexylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-(perfluorohexylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-25-acetyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-25-acetyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-25-(1-oxopropyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-25-(1-oxopropyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-25-(1-oxobutyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-25-(1-oxobutyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-25-acetyl-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-25-acetyl-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxopropyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxopropyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,25(R)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one
(5Z,7E,22E)-(1S,3R,25(S)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one
(5Z,7E,22E)-[1S,3R,25(R)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one
(5Z,7E,22E)-[1S,3R,25(S)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one
(5Z,7E,22E)-(3S,24R)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24S)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24R)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24S)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24R)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24S)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24R)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24S)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24R)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24S)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24R)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24S)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24R)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24S)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24R)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
(5Z,7E,22E)-(3S,24S)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-24-methoxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3diol
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-24-methoxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3diol
(5Z,7E,22E)-(1S,3R,24R)-25-hydroxymethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
(5Z,7E,22E)-(1S,3R,24S)-25-hydroxymethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-oxo-1-heptenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-oxo-1-heptenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E,E)]-(1S,3R,24R)-25-(1-oxo-2,4-hexadienyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
[5Z,7E,22E,25(E,E)]-(1S,3R,24S)-25-(1-oxo-2,4-hexadienyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
The natural vitamins D2 and D3 (cf. general formula of vitamin D) are inherently biologically inactive and are converted into biologically active metabolites [1xcex1,25-dihydroxy vitamin D3 (calcitriol) or -D2] only after hydroxylation at C-atom 25 in the liver and at C-atom 1 in the kidney. The action of the active metabolites involves the regulation of the calcium and phosphate concentration in the serum; they counteract a dropping of the calcium concentration in the serum by increasing the calcium absorption in the intestine and under certain circumstances promoting calcium mobilization from the bones. 
In addition to their pronounced effect on the calcium and phosphate metabolism, the active metabolites of vitamins D2 and D3 and their synthetic derivatives have a proliferation-inhibiting and differentiation-stimulating action on tumor cells and normal cells, such as, for example, skin cells. In addition, a pronounced effect on cells of the immune system (inhibiting of proliferation and interleukin 2-synthesis of lymphocytes, increase of cytotoxicity and phagocytosis in vitro of monocytes) has been found, which manifests itself in an immunomodulatory action, and finally, because of a stimulating action on bone-forming cells, an increased formation of bone in normal and osteoporotic rats is found [R. Bouillon et al. xe2x80x9cShort Term Course of 1,25(OH)2D3 Stimulates Osteoblasts But Not Osteoclasts.xe2x80x9d Calc. Tissue Int. 49, 168-173 (1991)].
All actions are mediated by bonding to the vitamin D receptor. Because of the bonding, the activity of specific genes is regulated.
When using biologically active metabolites of vitamins D2 and D3, a toxic effect on the calcium metabolism is produced (hypercalcemia).
By structural manipulations of the side chain, therapeutically usable effectiveness can be separated from undesirable hypercalcemic activity. A suitable structural variation is the introduction of 24-hydroxy derivatives.
1xcex1-Cholecalciferols that are hydroxylated in 24-position are already described in DE 25 26 981. They have a lower toxicity than the corresponding non-hydroxylated 1xcex1-cholecalciferol. Further, 24-hydroxy derivatives are described in the following patent applications: DE 39 33 034, DE 40 03 854, DE 40 34 730, EP 0 421 561, EP 0 441 467, WO 91/12238.
Finally, 25-carboxylic acid derivatives of calcitriol that are hydroxylated at C-24 are described in WO 94/07853, which exhibit a more advantageous spectrum of action than calcitriol. While the ability to trigger a hypercalcemia is considerably weakened, the proliferation-inhibiting and differentiation-stimulating actions are maintained.
Relative to these structurally allied compounds, the substances according to the invention are distinguished in that they show a greater effect on cell differentiation, whereby the effect on the calcium balance does not increase.
The vitamin D activity of the substances according to the invention is determined with the aid of the calcitriol-receptor test. It is carried out with use of a specific receptor protein from the intestines of juvenile pigs.
Receptor-containing binding protein is incubated in a test tube with 3H-calcitriol (5xc3x9710xe2x88x9210 mol/l) in a reaction volume of 0.270 ml in the absence and in the presence of test substances for two hours at 4xc2x0 C. To separate free and receptor-bound calcitriol, a charcoal-dextran absorption is carried out. 250 xcexcl of a charcoal-dextran suspension is fed to each test tube and incubated at 4xc2x0 C. for 20 minutes. Then, the samples are centrifuged at 10,000xc3x97g for 5 minutes at 4xc2x0 C. The supernatant is decanted and measured in a xcex2-counter after 1 hour of equilibration in Picofluor 15(trademark).
The competition curves that are obtained with various concentrations of test substance as well as of reference substance (unlabeled calcitriol) at constant concentration of the reference substance (3H-calcitriol) are placed in relation to one another and a competition factor (KF) is determined.
It is defined as a quotient of the concentrations of the respective test substance and the reference substance, which are necessary for 50% competition:
KF=Concentration of test substance at 50% competition/Concentration of reference substance at 50% competition
It is common to the compounds according to the invention that they all have a considerable affinity to the calcitriol receptor.
To determine the acute hypercalcemic action of various calcitriol derivatives, the test that is described below is carried out:
The action of control (solution base), reference substance (1,25(OH)2-D3=calcitriol) and test substance is tested in each case after one-time subcutaneous administration in groups of 10 healthy male rats (140-170 g). During the testing time, the rats are kept in special cages to determine the excretion of water and mineral substances. Urine is collected in 2 fractions (0-16 hours and 16-22 hours). An oral dose of calcium (0.1 mmol of calcium in 6.5% alpha-hydroxypropylcellulose, 5 ml/animal) replaces at 1600 hours the calcium intake that is lacking by food deprivation. At the end of the test, the animals are killed by decapitation and exsanguinated to determine the serum-calcium values. For the primary screen test in vivo, an individual standard dose (200 xcexcg/kg) is tested. For selected substances, the result is supported by establishing a dose-effect relation.
A hypercalcemic action is shown in serum-calcium level values that are higher than in the control.
The significance of differences between substance groups and controls and between test substance and reference substance are supported with suitable statistical processes. The result is indicated as dose ratio DR (DR=factor of test substance dose/reference substance dose for comparable effects).
The differentiation-stimulating action of calcitriol analogues is also detected quantitatively.
It is known in the literature (Mangelsdorf, D. J. et al., J. Cell. Biol. 98: 391-398 (1984)), that the treatment of human leukemia cells (promyelocyte cell line HL 60) in vitro with calcitriol induces the differentiation of cells to macrophages.
HL 60 cells are cultivated in tissue culture medium (RPMI 10% fetal calf serum) at 37xc2x0 C. in an atmosphere of 5% CO2 in air.
For substance testing, the cells are centrifuged off, and 2.0xc3x97105 cells/ml in phenol red-free tissue culture medium is taken up. The test substances are dissolved in ethanol and diluted with tissue culture medium without phenol red to the desired concentration. The dilution stages are mixed with the cell suspension at a ratio of 1:10, and 100 xcexcl each of this cell suspension that is mixed with substance is pipetted into an indentation of a 96-hole plate. For control, a cell suspension is mixed analogously with the solvent.
After incubation for 96 hours at 37xc2x0 C. in 5% CO2 in air, 100 xcexcl of an NBT-TPA solution (nitro blue tetrazolium (NBT), final concentration in the batch of 1 mg/ml, tetradecanoyl phorbolmyristate-13-acetate (TPA), final concentration in the batch of 2xc3x9710xe2x88x927 mol/l) is pipetted into each indentation of the 96-hole plate in the cell suspension.
By incubation for 2 hours at 37xc2x0 C. and 5% CO2 in air, NBT is reduced to insoluble formazan because of the intracellular oxygen radical release, stimulated by TPA, in the cells that are differentiated to macrophages.
To complete the reaction, the indentations of the 96-hole plate are suctioned off, and the cells are affixed to the bottom of the plate by adding methanol and dried after affixing. To dissolve the intracellular formazan crystals that are formed, 100 xcexcl of potassium hydroxide (2 mol/l) and 100 xcexcl of dimethyl sulfoxide are pipetted into each indentation and ultrasonically treated for 1 minute. The concentration of formazan is measured by spectrophotometry at 650 nm.
As a yardstick for the differentiation induction of HL 60 cells to macrophages, the concentration of formed formazan applies. The result is indicated as a dose ratio (DR=factor of test substance dose/reference substance dose for comparable semi-maximum effects).
The results of the calcitriol-receptor test and the determination of the dose ratio of the differentiation induction of HL 60 cells and the dose ratio for hypercalcemia are summarized below (Tab. 1):
Selected Test Compounds
(5Z,7E,22E)-(1S,3R,24R)-25-Acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 7b
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 8b
(5Z,7E,22E)-(1S,3R,24R)-25-benzoyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 10b
(5Z,7E,22E)-(1S,3R,24R)-25-(cyclopropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 12b
(5Z,7E,22E)-(1S,3R,24R)-25-(2,2-dimethyl-1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 15b
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxo-2-hexinyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 19b
(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 33a
(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 33b
(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 35a
(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 35b
(7E,22E)-(1R,3R,24R)-25-acetyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol 55b
(7E,22E)-(1R,3R,24S)-25-acetyl-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol 81a
(7E,22E)-(1R,3R,24R)-25-acetyl-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol 81b
Comparison Compound
Calcitriol
In addition to an affinity to the vitamin D receptor, which is comparable to that of calcitriol, the compounds listed partially show a greater cell-differentiating activity.
The induction of a hypercalcemia is carried out, however, only at very much higher doses than in the case of calcitriol (e.g., dose ratio for 7b=300, 8b=100, 15b=300, 19b greater than 300, calcitriol DR=1).
By the reduced property of triggering a hypercalcemia, the substances according to the invention are suitable in a special way for the production of pharmaceutical agents for the treatment of diseases that are characterized by hyperproliferation and deficient cell differentiation. Included in these are, for example, hyperproliferative diseases of the skin (psoriasis, pityriasis subia pilasis, acne, ichthyosis) as well as tumor diseases and precancerous stages (for example, tumors of the intestines, carcinomas of the breast, lung tumors, prostate carcinomas, leukemias, T-cell lymphomas, melanomas, Batazell Larzin, squamous carcinoma, actinic keratoses, cervix dysplasias, metastasizing tumors of any type).
Also, for the treatment and prophylaxis of diseases that are characterized by a disequilibrium of the immune system, the substances according to the invention are suitable. These include eczemas and diseases of the atopic Formon series, as well as auto-immune diseases, such as, for example, multiple scleroses, diabetes mellitus type I, myasthenia gravis, lupus erythematosus, scleroderma, bullous skin diseases (pemphigus, pemphigoid), further rejection reactions in the case of autologous, allogeneic or xenogeneic transplants, as well as AIDS. In all these diseases, the new compounds of general formula I can be combined advantageously with other substances that have an immunosuppressive action, such as cyclosporin A, FK 506, rapamycin and anti-CD 4 antibodies.
The substances are also suitable for therapy of secondary hyperparathyroidism and renal osteodystrophia because of the property of calcitriols to drop the parathormone synthesis.
Owing to the presence of the vitamin D conceptor in the insulin-producing cells of the pancreas, the substances are suitable by increasing the insulin secretion for the therapy of diabetes mellitus type II.
Further, it has been found, surprisingly enough, that by topical application of the compounds according to the invention on the skin of mice, rats and guinea pigs, an increased reddening of the skin and increase of the thickness of the epidermis can be induced. The increase in the reddening of the skin is determined from the increase in the red value of the skin surface that can be quantified with a calorimeter. The red value is typically increased 1.5-fold after the substance (dose 0.003%) is administered three times at intervals of 24 hours. The increase of the thickness of the epidermis is quantified in the histological preparation. It is typically increased 2.5-fold. The number of proliferating epidermal cells (cells in the S-phase of the cell cycle) is determined by flow cytometry and is typically increased by a factor of 6.
These properties of the 25-carboxylic acid derivatives in the vitamin D series according to the invention can appear suitable for therapeutic use in the case of atrophic skin, as it occurs in natural skin aging because of increased light exposure or medicinally-induced skin atrophy by treatment with glucocorticoids.
Further, it can be assumed that wound healing can be accelerated by topical application with the new compounds.
In cell populations of the hair follicle, which contribute decisively to hair growth or to hair cycle regulation, it was possible to detect vitamin D3 receptor proteins (Stumpf, W. E. et al., Cell Tissue Res. 238: 489-496; Milde, P. et al., J. Invest., 97: 230-239, 1991). In addition, in vitro findings on isolated hair follicle keratinocytes show a proliferation-inhibiting and differentiation-stimulating influence of 1,25-(OH)2-D3.
From clinical observations, it is known that the vitamin D3-resistant rickets often accompanies alopecia, which develops in early infancy. Experimental findings show that the vitamin D3 bonding site of the VDR in this disease mutates, i.e., is defective (Kristjansson, K. et al., J. Clin. Invest. 92: 12-16, 1993). Keratinocytes, which were isolated from the hair follicles of these patients, do not react in vitro to the addition of 1,25-(OH)2-D3 (Arase, S. et al., J. Dermatol. Science 2: 353-360, 1991).
These findings indicate a decisive role for 1,25 D3 in the regulation of hair growth.
These analogues are therefore especially suitable for the production of pharmaceutical agents for the treatment of diseases which accompany disrupted hair growth (androgenetic alopecia, alopecia areata/totalis, chemotherapy-induced alopecia) or for supporting physiological hair growth.
Senile and postmenopausal osteoporosis is characterized by an increased bone turnover with an overall negative balance. Owing to the bone shrinkage especially of trabecular bones, fractures result to an increased extent. Owing to the stimulating action of calcitriol, both in the number and the conduct of synthesis of cells forming new bones (osteoblasts), the substances according to the invention are suitable for therapy and prophylaxis of senile and postmenopausal osteoporosis (EP 0 634 173 A1), of steroid-induced osteoporosis as well as for accelerated healing of arthroplasties. For the therapy of various forms of osteoporosis, they can be combined advantageously with estradiol or other derivatives of estrogen.
Finally, it was possible to show that calcitriol increases the synthesis of a growth substance for nerve cells (nerve growth factor) [M. S. Saporito et al. Brain Res. 633, 189-196 (1994)]. The compounds according to the invention are therefore also suitable for treating degenerative diseases of the peripheral and central nervous system, such as Alzheimer""s disease and amyotrophic lateral sclerosis.
In addition, it has been found that certain compounds of general formula I in HL 60 cells antagonize, surprisingly enough, the action of calcitriol. In the series of 25-alkyl derivatives, the compounds with increasing chain length on the carbonyl group in the case of constantly good receptor affinity show considerably weaker differentiation-stimulating agonistic activity in HL 60 cells (Tab. 2).
Selected Test Compounds with Antagonistic Action
(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 6b
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 9b
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-oxo-2-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 18b
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-ethoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 24b
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 26b
(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 43a
(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 43b
(7E,22E)-(1R,3R,24R)-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol 58b
(7E,22E)-(1R,3R,24R)-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol 61b
(7E,22E)-(1R,3R,24S)-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol 64a
(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol 61b
Comparison Compound
Calcitriol
The compounds 6b, 9b, 18b, 24b, 26b, 43a, 43b, 58b, 61b, 64a and 87b antagonize the action of calcitriol in HL 60 cells. This property is continued with increasing chain length in radical Z of general formula I.
Such compounds that antagonize the action of calcitriol can be used for the therapy of hypercalcemias, such as, for example, in hypervitaminosis D or intoxication with calcitriol and calcitriol-like active substances, or in the case of increased extrarenal calcitriol synthesis in granulomatous diseases (sarcoidosis, tuberculosis). Also, paraneoplastic hypercalcemias (for example, in osteolytic metastases and tumors with increased synthesis of parathormone-related peptides) as well as in hypercalcemias in hyperparathyroidism.
In addition, calcitriol antagonists can be used for birth control. In the reproductive tracts of female and male animals, the vitamin D receptor is expressed. It is known that the female and male fertility of vitamin-D-deficient animals is reduced. By short-term substitution of calcitriol, the reproductive output can be increased. Calcitriol antagonists are therefore able to influence female and male fertility.
Since calcitriol, under certain conditions, shows an immunosuppressive action, calcitriol receptor antagonists can also be used as immunostimulants, e.g., in the case of weak defenses against infections.
Calcitriol is known to be able to modulate hair growth. Calcitriol antagonists can therefore be used therapeutically in the case of undesirable hair growth, e.g., in hirsutism.
Vitamin D has long been known to play a stimulating role in the formation of arteriosclerotic plaque. In such vascular lesions, a calcitriol-regulated protein, osteopontin, is found to be increased, to which a role in vascular sclerosis is attributed [R. Eisenstein et al. Arch. Path. 77, 27-35 (1964), L. A. Fitzpatrick et al., J. Clin. Invest. 94, 1597-1604 (1994)]. Calcitriol antagonists are therefore suitable for therapy and prophylaxis of all types of arteriosclerosis.
Finally, calcitriol antagonists are suitable because of the property of calcitriol to increase unspecific immune reactions of monocytic cells, for therapy of inflammatory diseases, especially of a chronic nature, such as rheumatoid arthritis, Crohn""s disease, ulcerative colitis, and granulomatous diseases such as sarcoidosis and other foreign-body reactions.
This invention thus relates to pharmaceutical preparations that contain at least one compound according to general formula I together with a pharmaceutically compatible vehicle.
The compounds can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicles or as pills, tablets or capsules, which contain solid vehicles in a way known in the art. For topical use, the compounds are advantageously formulated as creams or ointments or in a similar form of pharmaceutical agent that is suitable for topical use. Each such formulation can also contain other pharmaceutically compatible and nontoxic adjuvants, such as, e.g., stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring additives. The compounds are advantageously administered by injection or intravenous infusion of suitable sterile solutions or as oral dosage via the alimentary tract or topically in the form of creams, ointments, lotions or suitable transdermal patches, as is described in EP-A 0 387 077.
The daily dose is approximately 0.1 xcexcg/patient/dayxe2x80x941000 xcexcg (1 mg)/patient/day, preferably 1.0 xcexcg/patient/day-500 xcexcg/patient/day.
The production of the vitamin D derivatives of general formula I is carried out according to the invention from a compound of general formula II, 
in which Yxe2x80x21 means a hydrogen atom or a protected hydroxy group and Yxe2x80x22 means a hydroxy protective group.
The protective groups are preferably alkyl-, aryl- or mixed alkylaryl-substituted silyl groups, e.g., the trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) or truisopropylsilyl (TIPS) groups or another standard hydroxy protective group (see T. W. Greene, P. G. M. Wuts xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d 2nd Edition, John Wiley and Sons, 1991).
Axe2x80x2 and Bxe2x80x2 together can mean a keto group or one of the two substituents can mean an optionally protected hydroxy group and the other a hydrogen atom (e.g., silyl protective group of the above definition, tetrahydrofuranyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl or trimethylsilylethoxymethyl group).
Zxe2x80x2 can have a meaning analogous to Z or optionally exhibit protective group-carrying substituents (e.g., hydroxy protective groups according to the above definition).
By simultaneous or successive cleavage of the hydroxy protective groups and optionally by partial, successive or complete esterification of the free hydroxy groups, II is converted to a compound of general formula I.
In the case of the silyl protective groups or the trimethylsilylethoxymethyl group, tetrabutylammonium fluoride, hydrofluoric acid or hydrofluoric acid/pyridine is used for their cleavage; in the case of the other ether groups, the latter are cleaved under catalytic action of acid, for example, p-toluenesulfonic acid, pyridinium-p-toluenesulfonate, acetic acid, hydrochloric acid, phosphoric acid or an acidic ion exchanger.
The esterification of the free hydroxy groups can be carried out according to standard processes with the corresponding carboxylic acid chlorides, bromides or anhydrides.
Separations of diastereomers (e.g., relative to C-24) can be carried out in the final stage or any other preliminary stage.
The production of the starting compounds for general formula II starts from various starting compounds depending on the ultimately desired substitution pattern in 10- and 20-position.
For the production of compounds of general formula II, in which R1 and R2 together mean an exocyclic methylene group, a start is made from known aldehyde III [M. Calverley Tetrahedron 43, 4609 (1987), WO 87/00834]. 
For Yxe2x80x21 and Yxe2x80x22, the already mentioned definitions apply. Protective groups other than those mentioned in the bibliographic references can be obtained by analogous procedure using correspondingly modified silyl chlorides (e.g., tert-butyldiphenylsilyl chloride instead of tert-butyldimethylsilyl chloride). By foregoing the corresponding stages for 1xcex1-hydroxylation, derivatives of Yxe2x80x21xe2x95x90H type can be obtained.
The compounds of general formula III are now converted, analogously to known processes, into aldehydes of general formula IV (WO 94/07853). 
For R3 and R4, the definitions that are already mentioned above apply.
In building the side chain, both compounds of general formula III and compounds of general formula IV can now be used. By way of example, the reaction of compounds of general formula III is described below. Analogously to the established sequence (WO 94/07853), carboxylic acid amides of general formula V can thus be generated, 
whereby for Yxe2x80x21, Yxe2x80x22, R5 and R6, the already given definitions apply. Preferably, R5 and R6 each are to mean a methyl group or both together with carbon atom 25 mean a cyclopropyl ring. R7 and R8 mean straight-chain or branched-chain alkyl groups with 1-9 carbon atoms, whereby especially methyl and ethyl groups are preferred.
Reduction of the keto group with reducing agents, such as, e.g., NaBH4 or NaBH4/CeCl3, then results in alcohols of general formula VI. 
To establish the natural vitamin D-triene system, a photochemical isomerization of the compounds of general formula VI is performed. Irradiation with ultraviolet light is carried out in the presence of a so-called triplet sensitizer. Within the scope of this invention, anthracene is used in this respect. By cleavage of the xcfx80-bond of the 5,6-double bond, rotation of the A ring by 180xc2x0 around the 5,6-single bond and reestablishing the 5,6-double bond, the stereoisomerism on the 5,6-double bond is reversed, whereby compounds of general formula VII result, 
whereby Yxe2x80x21, Yxe2x80x22, R5, R6, R7 and R8 have the above-mentioned meanings. The diastereomeric alcohols at C-24 can be separated by chromatography.
In building radical Zxe2x80x2, compounds of general formula VII are reacted at low temperature (xe2x88x92100 to 0xc2x0 C.) with suitable lithium organyls of general formula VIII
LiR9xe2x80x83xe2x80x83VIII
The lithium organyls can be generated under standard conditions (halogen-lithium exchange in the case of haloalkanes, metalizations of aromatic or heteroaromatic systems, metal-lithium exchange, definitions for R9 were already mentioned). In this case, compounds of general formula II result, whereby for Yxe2x80x21, Yxe2x80x22, R5 and R6, the above-mentioned meanings apply; R1 and R2 together mean an exocyclic methylene group; R3 and R4 depending on the selection of aldehyde III or IV have the meanings derived from them; Axe2x80x2 is a hydroxy group and Bxe2x80x2 is a hydrogen atom or Axe2x80x2 is a hydrogen atom and Bxe2x80x2 is a hydroxy group, and Zxe2x80x2xe2x95x90C(O)xe2x80x94R9. The hydroxyl group in 24-position (Axe2x80x2 or Bxe2x80x2) can be converted before the final protective group cleavage optionally with an oxidizing agent such as, e.g., PCC, PDC, BaMnO4, MnO2, Swern conditions, Dess-Martin reagent to a 24-ketone of general formula II, whereby Axe2x80x2 and Bxe2x80x2 together form a keto group. The subsequent protective group cleavage must then be carried out, however, under acidic reaction conditions (e.g., acidic ion exchanger, acetic acid, p-toluenesulfonic acid, pyridinium-p-toluenesulfonate), since when using the usual fluoride reagents, conjugated additions of nucleophiles to the enone system are to be feared. A temporary protection of the 24-hydroxy group can be carried out with a protective group as in Yxe2x80x21 and Yxe2x80x22 to increase in some cases the yield in the addition of lithium-organic compound VIII.
If sterically exacting, branched radicals are to be established for R9, the reaction of the known ester of general formula IX (WO 94/07853) instead of amide VII is carried out with lithium-organic compound VIII, whereby a compound of general formula II results. 
Radical R10 means a straight-chain or branched-chain alkyl group with 1-9 carbon atoms.
In principle, the diastereomeric alcohols (relative to C-24) in the case of the above-mentioned sequences can be reacted separated in advance and reacted separately.
For the synthesis of additional modified derivatives, the compound of general formula IX is converted by protection of the 24-hydroxy group into a compound of general formula X, 
whereby R11 means an acid-labile protective group that has a definition analogous to Yxe2x80x21 or Yxe2x80x22 or the tetrahydropyranyl, tetrahydrofuranyl, ethoxyethyl, methoxymethyl or methoxyethoxymethyl group. By reduction of the ester unit of general formula X with a reducing agent such as, e.g., DIBAH, TIBA, LiAlH4, RedAl, compounds of general formula XI 
are obtained.
Under the known reaction conditions, ethers, sulfides and amines can now be generated, whereby compounds of general formula II result, for which Zxe2x80x2xe2x95x90Xxe2x80x94R9, with Xxe2x95x90O, S, NH, N-alkyl, N-acyl.
For further structural variation, the compounds of general formula XI can be reacted to the aldehydes of general formula XII. 
This reaction can be carried out with the reagents or methods already indicated for the oxidation of the hydroxy group in 24-position. In addition to the already mentioned lithium organyls of general formula VIII, whose use here results in compounds of general formula II, whereby Zxe2x80x2xe2x95x90CH(OH)xe2x80x94R9, perfluorinated alkyl radicals can be introduced here according to methods known in the literature [G. K. Surya Prakash J. Org. Chem. 56, 984 (1991), H. Uno et al. Bull. Chem. Soc. Jpn. 62, 2636 (1989)]. By catalytic action of tetrabutylammonium fluoride on the readily available perfluoroalkyltrimethylsilanes (synthesis from the commercially available perfluoroalkyl iodides) or by iodine-lithium exchange of the perfluoroalkyl iodides with methyllithium/lithium bromide complex, an attack on the carbonyl group can be carried out, whereby after hydrolytic working-up, compounds of general formula XIII result, 
whereby R9 can mean straight-chain or branched-chain perfluorinated alkyl radicals that have 1-9 carbon atoms. The diastereomeric alcohols are separated by chromatography. The compounds of general formula XIII, on the one hand, can be considered a special case of general formula II and can be further treated as described there or, on the other hand, can be converted by oxidation with one of the already previously mentioned oxidizing agents (preferably Swern conditions or Dess-Martin reagent) into a compound of general formula II, whereby Zxe2x80x2xe2x95x90C(O)xe2x80x94R9.
Aldehyde XII can also be reacted with Wittig, Wittig-Horner or Wadsworth-Emmons reagents of type XIV 
whereby V=C1-C8 alkyl or alkoxy (straight-chain or branched-chain or cyclic) preferably mean methyl, methoxy, ethyl, ethoxy, butyl, butoxy, phenyl, phenoxy and the definition for R12 was already given above, in the presence of bases (e.g., NaH, KH, LDA, butyllithium, LiHMDS, NaHMDS, KHMDS), to compounds of general formula XV, 
which can be considered a special case of general formula II, for which: 
The aldehyde of general formula XII can also be converted by using methods known in the literature [L. Van Hijfte Tetrahedron Lett. 30, 3655 (1989), S. L. Schreiber J. Am. Chem. Soc. 112, 5583 (1990), J. R. Hauske Tetrahedron Lett. 33, 3715 (1992)] into compounds of general formula XVI, 
which can be considered a special case of general formula II, whereby 
The production of compounds of general formula I, if R1 and R2 mean hydrogen atoms, is carried out in that a compound of general formula IIxe2x80x2, 
whereby the already mentioned meanings exist for Yxe2x80x22, R3, R4, R5, R6, Axe2x80x2, Bxe2x80x2 and Zxe2x80x2, is treated analogously to the conditions that are described for the reaction of II.
The production of compounds of general formula IIxe2x80x2 is carried out in a convergent synthesis method, whereby CD and A-ring fragments are separately structured. For synthesis of the CD fragments, aldehyde XVII, known in the literature [H. H. Inhoffen et al. Chem. Ber. 91, 780 (1958), Chem. Ber. 92, 1772 (1959), W. G. Dauben 30, 677 (1989)] is used, 
in which P means an acyl-, alkyl- or aryl-substituted silyl or tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, ethoxyethyl group, an acyl group (e.g., acetyl, benzoyl) or another alcohol protective group (see T. W. Greene, P. G. M. Wuts xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d 2nd Edition, John Wiley and Sons, Inc., 1991).
According to the known process (WO 94/07853), the modifications at C-20 that are already described for the normal series can be introduced, whereby a compound of general formula XVIII results. 
For R3 and R4, the above-mentioned definitions apply.
For simplification and by way of example, the reaction of the compound of general formula XVII is described below.
If R5 and R6 together with tertiary carbon atom 25 form a cyclopropyl ring, as known for the normal series (WO 94/07853), by aldol reaction with an acetoacetic ester component of general formula XIX, 
whereby R means a straight-chain alkyl group with 1-6 carbon atoms, a compound of general formula XX can be obtained. 
Via intermediate products XXI, XXII and XXIII, the compound of general formula XXIV is then available. 
The chemical manipulations that are necessary in this respect as well as the meanings of P, R7, R8, R9 and R11 have already been described elsewhere. By reduction of the keto group with a reducing agent (e.g., NaBH4, NaBH4/CeCl3, LiAlH4, DIBAH, TIBA, RedAl), a compound of general formula XXV is available, whose hydroxy group is provided with an acid-stable protective group that is to be removed by basic action (e.g., R14=acetyl, propionyl, pivaloyl, benzoyl group), whereby a compound of general formula XXVI is obtained. Separations of diastereomeric hydroxy groups are carried out in each case in suitable intermediate stages. 
In the selection of suitable protective groups (e.g., Pxe2x95x90Et3Si, R11xe2x95x90THP, R14xe2x95x90Ac), group P can be selectively cleaved and by oxidation of the hydroxy group, the compound of general formula XXVII can be converted with an oxidizing agent (PCC, PDC, BaMnO4, Swern conditions, Dess-Martin reagent) into a CD fragment of general formula XXVIII. 
The compounds of general formula XXVIII are now converted by reaction with the anion of the phosphine oxide of general formula XXIX, known in the literature, that is produced by a base such as n-butyllithium or LDA [H. F. DeLuca et al. Tetrahedron Lett. 32, 7663, (1991)], 
in which Yxe2x80x22 has the already described meaning, into the corresponding compounds of general formula XXX. 
Successively or simultaneously, the protective groups are now removed (R14 by basic hydrolysis, R11 as well as Yxe2x80x22 by acid hydrolysis or fluoride reagents) and, as desired, one or both of the side chain hydroxy groups are oxidized with the already frequently mentioned oxidizing agent, whereby compounds of general formula I result, for which: R1 and R2 are hydrogen atoms and R5 and R6 together with tertiary carbon atom 25 form a cyclopropyl ring. The additional definitions were already mentioned.
As an alternative, protective group P in general formula XXIII can be selectively cleaved, if: P=silyl protective group, R11=tetrahydropyranyl or tetrahydrofuranyl protective group. This can be carried out, e.g., with tetrabutylammonium fluoride, whereby compounds of general formula XXXI result. 
The free hydroxy group can now be oxidized with an oxidizing agent (PCC, PDC, BaMnO4, Swern conditions, Dess-Martin reagent), whereby compounds of general formula XXXII are produced, 
which are converted with the anion of phosphine oxide XXIX that is produced by a base (n-butyllithium, lithium diisopropylamide) into compounds of general formula XXXIII. 
Analogously to the compounds in the normal series (e.g., VII), the building of radical Zxe2x80x2 now takes place, whereby compounds of general formula XXXIV result. 
These can be considered a special case of general formula IIxe2x80x2, whereby all variables have already been described previously. The further treatment of the compounds of general formula IIxe2x80x2 has also been indicated above.
If R5 and R6 do not form a cyclopropyl ring together with tertiary carbon atom 25, rather the other above-mentioned definitions are to apply, the building of the side chain takes place with a somewhat modified synthesis method. The known CD-portion of general formula XXXV (WO 94/07853) can be converted, analogously to the normal series, into derivatives of general formulas XXXVI and XXXVII, 
whereby all variables have the already mentioned definitions. The diastereomers can be separated into suitable intermediate stages.
By direct reaction of the lithium organyls of general formula VIII (LiR9) with compounds of general formulas XXXVI and XXXVII, compounds of general formula XXXVIII can now be generated, and as shown before, are converted into a compound of general formula IIxe2x80x2.
The diastereomeric alcohols (relative to C-24) can be reacted separated in advance and reacted separately. 
In principle, the introduction of correspondingly substituted side chains or their precursors can also be carried out on aldehydes of general formulas III or IV or their 5Z-isomers with use of established synthesis methods.
The following examples are used for a more detailed explanation of the invention.